Malaria during pregnancy kills thousands of mothers and hundreds of thousands of infants each year, so prevention is essential, but current regimens are losing efficacy to drug-resistant parasites. Scientists submitting this grant application have been conducting longitudinal studies and interventional trials of antimalarial drugs in pregnant women and young children in Tanzania. These studies indicate that placental malaria is common despite widespread delivery of Intermittent Presumptive Treatment to Pregnant women (IPTp) in Tanzania. In these studies, placental malaria increases the frequency of parasitemia and increases the frequency of all-cause hospitalization during infancy and early childhood, and retards weight gain during infancy. Taken together, the results indicate a public health crisis for Tanzanian mothers and their newborns who urgently require information on new malaria preventative regimens during pregnancy. In the studies proposed here, three new IPTp regimens (chlorproguanil-dapsone (LapDap); mefloquine; sulfadoxine-pyrimethamine (SP) + azithromycin) will be compared to the currently recommended regimen (SP alone) for their efficacy and safety, including longterm effects on neurodevelopmental outcomes of offspring. Regimens will also be compared for their effect on protective antibody levels, placental inflammation, infant development, and infant susceptibility to malaria infection and disease. The scientists submitting this grant application are uniquely qualified to carry out the research. This proposed program is based on the following hypotheses: IPTp with new regimens will be safe for mothers and their offspring, and will improve pregnancy outcomes among malaria-exposed women; effective IPTp regimens will delay the acquisition of protective antibodies against placental parasites, but will also prevent placental inflammation; effective IPTp will reduce susceptibility to malaria infection and disease during early life, and will improve measures of infant development; a center of excellence can be developed in Tanzania that is focused on malaria interventional studies for pregnant women and children. The Program will be organized as three discrete but inter-related projects, supported by a Data and Biostatistics Core. Our broad, long-term objectives are to identify more effective treatments to prevent malaria infection and disease in pregnant women, and to understand the long-term impact of malaria prevention on the acquisition of protective immunity and malaria susceptibility in pregnant women and their infants. We will also establish a center of excellence for future research on antimalarial interventions in Tanzania.